Abstract
Background:
Buprenorphine is an effective treatment for opioid use disorder, but it can be challenging to avoid withdrawal in the process of buprenorphine initiation. After the recent FDA approval of 7-day long-acting injectable buprenorphine, some clinicians have used this formulation to start patients on buprenorphine without a prior sublingual “test dose.” Very little is known about the feasibility of this practice in an outpatient setting.
Cases:
In this case series, we conducted a retrospective chart review of electronic health record data for all patients who were ordered 7-day long-acting injectable buprenorphine for a “direct-to-inject” initiation within a single public health system from January 1, 2024 to November 15, 2024. We excluded patients who received a cumulative dose of 4 mg or more of sublingual buprenorphine in the 24 hours before injection. We reported on chart-documented patient experiences after injection, whether patients returned to care, and retention on buprenorphine at 7- and 30-days post-injection. We identified 21 unique patients who received direct-to-inject buprenorphine in 22 attempts. In 17 (77%) attempts, the patient received no buprenorphine in the preceding 24 hours. In 5 (23%) attempts, patients received some buprenorphine in the preceding 24 hours (<4 mg) and/or had evidence of buprenorphine in a same-day urine drug screen. Patient experiences post-injection fit into 1 of 3 themes: “It felt fine” (n = 6), “I felt unwell but okay” (n = 13), and “It felt very rough” (n = 3). Most attempts resulted in buprenorphine treatment retention at 7 days (n = 17, 77%) and 30 days (n = 16, 73%) after injection.
Discussion:
Direct-to-inject buprenorphine was generally well tolerated, with excellent retention on buprenorphine at 7- and 30 days post-injection. Further research is needed to evaluate the correlation between preinjection patient characteristics (time since last use, level of withdrawal) and post-injection patient experience of withdrawal.
Highlights
Outpatient direct-to-inject 7-day buprenorphine initiation was well tolerated in our case series.
Most patients experienced mild-to-moderate withdrawal symptoms.
About three-fourths of attempts led to retention in buprenorphine treatment at 30 days.
Introduction
Buprenorphine is an effective, well-tolerated treatment for opioid use disorder (OUD). 1 Initiating buprenorphine can be difficult; it typically requires patients to either wait for at least moderate opioid withdrawal (traditional initiation) or gradually escalating doses of buprenorphine over multiple days while using full-agonist opioids (low-dose initiation). Patients may struggle with both approaches, in part due to the risk of withdrawal. 2 Further, the risk of precipitated withdrawal is theorized to be higher in patients using fentanyl than other opioids, which is concerning as fentanyl has come to dominate the North American drug supply and has been responsible for the majority of opioid-related deaths in the United States.3,4
Notably, 7-day long-acting injectable buprenorphine (CAM2038, Brixadi®) 5 is approved for use in patients with moderate-to-severe withdrawal, after a sublingual “test dose” of buprenorphine 4 mg or higher. One recent study from emergency departments has described the novel practice of “direct-to-inject” buprenorphine initiation. 6 In direct-to-inject initiations, patients receive an injection of 7-day extended-release buprenorphine without a prior test dose, to lower the risk of the test dose precipitating withdrawal in patients with recent opioid use. The comparatively slow onset of the 7-day formulation of extended-release buprenorphine compared to sublingual formulations, with peak serum levels occurring at approximately 24 hours post-injection, may reduce withdrawal severity by more gradually displacing full opioid agonists from the mu-opioid receptor, thereby mimicking low-dose buprenorphine initiation protocols and theoretically lowering the risk of precipitated withdrawal. 7 Preliminary data from the Emergency Department (ED) context show direct-to-inject buprenorphine is well tolerated with 1 prospective study showing low rates of severe withdrawal in the first 4 hours after direct-to-inject buprenorphine initiation in several EDs across the United States. 6 However, almost half of the participants in the study had recent buprenorphine exposure with urine toxicology results positive for buprenorphine. It is therefore important to understand whether patients with any buprenorphine in their system prior to injection could be less likely to experience significant withdrawal after direct-to-inject initiation compared to those with no prior buprenorphine exposure.
In addition, there is little published data on direct-to-inject initiations in the outpatient setting. One small outpatient case series suggests the feasibility of direct-to-inject among patients using heroin or transitioning from methadone, 8 but to our knowledge, there is no published data about the tolerability, patient experience, and outcomes for direct-to-inject buprenorphine for patients in outpatient settings, particularly among patients using fentanyl. We present a case series describing the use of direct-to-inject buprenorphine across multiple outpatient clinical sites in a single public health system in the United States to help inform clinical practice and future research.
Cases
Methods
Study Settings and Population
We conducted a retrospective chart review of electronic health record data of direct-to-inject buprenorphine initiations from a single, safety-net public health system. Six clinical sites offered direct-to-inject initiation to patients in our health system, including 2 outpatient addiction clinics, 1 psychiatry clinic, and 1 low-barrier site for HIV, Hepatitis C, and sexually transmitted infection prevention and treatment, a street medicine clinic, and permanent supportive housing outreach. Patients interested in initiating buprenorphine meet with a licensed clinician to discuss treatment options. All patients with OUD were eligible for direct-to-inject initiation, regardless of prior experiences with buprenorphine. Some clinics used internal guidelines for direct-to-inject buprenorphine to guide care, but direct-to-inject approaches were generally individualized based on clinician judgment, with variations in injection doses, waiting times between last use and injection, and management of post-injection symptoms. Timing of subsequent sublingual and weekly or monthly injectable doses also varied. For example, 1 patient received an additional weekly injection 2 days after the direct-to-inject dose, with a monthly injection given on day 7 after the first dose, while another took supplemental sublingual buprenorphine for 3 days after the first dose and received a monthly injection on day 4.
Study Data and Measures
We extracted electronic health record data on all patients who received 7-day long-acting injectable buprenorphine across all sites from January 1, 2024 to November 15, 2024. We reviewed all records and included patients aged ≥18 years who received the 7-day long-acting injectable to initiate buprenorphine treatment. Patients who had taken ≥4 mg of sublingual buprenorphine in the preceding 24 hours or were on daily doses of buprenorphine in the last 7 days were excluded. We reviewed the charts of all remaining patients to confirm they had received direct-to-inject buprenorphine initiation and included them in the study.
We categorized patients as either having “no buprenorphine prior to injection” or “recent buprenorphine exposure prior to injection,” with recent exposure defined as either documented receipt of <4 mg in the preceding 24 hours or same-day urine drug screen prior to injection being positive for buprenorphine.
We reported measures including age, gender, race and ethnicity, patient-reported opioid use, prior buprenorphine and/or methadone attempts, other substance use, Clinical Opiate Withdrawal Scale (COWS) score preinjection, time of last opioid use, and dose of injection. Race and ethnicity were collected from patient electronic health records. These data fields were collected because racism affects multiple aspects of substance use disorder treatment.9-11 Traditional buprenorphine initiation guidelines prior to significant fentanyl in the drug supply typically recommend giving buprenorphine at COWS
We examined free-text clinician notes describing patient-reported experiences in the first 24 hours post-injection and extracted descriptions of withdrawal severity. Where present in the medical record, we included direct quotations from patients about their subjective experience, as captured by providers in the notes. Two authors, through iterative discussion, analyzed these descriptions, identified 3 distinct thematic groups, and categorized clinician descriptions and patient descriptions of experience accordingly. We did not explicitly assess for precipitated withdrawal, as we did not have detailed information on the withdrawal timeline for these patients who received buprenorphine in a clinic setting, and little is known about how precipitated withdrawal would manifest with the gradual onset of 7-day long-acting injectable buprenorphine.
We also assessed return to care (defined as attending a post-injection follow-up visit), buprenorphine retention at 7 ± 2 days, and buprenorphine retention at 30 ± 7 days using pharmacy data.
We defined buprenorphine retention at 7 days as either having received an additional long-acting injection or having received and endorsed taking a sublingual buprenorphine prescription at 5 to 9 days post-injection. We added flexibility of 2 days at either end in accordance with the package insert stating the medication can be given 2 days early or late. 12 We specifically wanted to account for receipt of additional buprenorphine during the window where we would expect the therapeutic effect of a single dose of long-acting injectable buprenorphine to wane (eg, if a patient received additional sublingual buprenorphine the day after their injection but received no further buprenorphine, we would not consider the patient to be retained on buprenorphine at 7 days). Our 30-day endpoint was defined similarly, with the flexibility of a week at either end in accordance with the monthly buprenorphine package insert. 12
Statistical Analysis
We used descriptive statistics to describe patient and treatment attempt characteristics. We used “recent buprenorphine exposure” as our main exposure of interest and used bivariate testing to compare differences in characteristics and outcomes between the 2 groups. We also examined the association between categories of preinjection COWS and subjective withdrawal experiences, as well as the association between subjective withdrawal experiences and subsequent retention using bivariate testing. Bivariate tests included the Wilcoxon rank-sum test for continuous outcomes and Fischer’s exact test for categorical outcomes with expected cell counts of less than 5. All analyses were done in Stata Version 16.0 (Stata Corp, College Station, TX, USA). We followed Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for observational research. 13
Results
We identified 21 unique patients who received direct-to-inject buprenorphine through 22 initiation attempts.
Of the 21 patients, the median age was 40 (interquartile range 33-49) with 14 (67%) men and 7 (33%) women. Most patients were White (7, 33%) or Hispanic, Latino/a, or Spanish origin (7, 33%). The majority used fentanyl (14, 67%); 5 (24%) used heroin, and 2 (10%) used other opioids (ie, methadone and non-prescribed opioid pills). There was a high percentage of concurrent methamphetamine use (12, 52%). All patients had prior buprenorphine experience, and 16 patients had prior methadone experience (Table 1).
Demographic Characteristics of Patients With Opioid Use Disorder Initiating Buprenorphine Using Direct-to-Inject 7-Day Extended-Release Buprenorphine Injection (n = 21).
Defined as having received <4 mg SL in the previous 24 hours and/or positive buprenorphine on available urine drug screen; bIncluded methadone and pressed pills; cNot mutually exclusive.
In the 8 initiation attempts that had urine drug screens available, 2 were positive for buprenorphine. In neither case were the patients stable on buprenorphine—in 1 case, the patient had received a dose of buprenorphine in jail 3 to 4 days prior to injection. In the other, the patient reported that their last use of buprenorphine was a week prior to injection.
Out of 22 buprenorphine initiation attempts, 17 (77%) were defined as having no recent buprenorphine exposure. Five attempts (23%) had some recent buprenorphine exposure: of these, 2 attempts had buprenorphine-positive urine drug screens and 3 attempts were in patients who had received <4 mg of buprenorphine in the 24 hours preinjection or had received few doses of sublingual buprenorphine a few days prior (Table 2).
Treatment Characteristics and Outcomes of Buprenorphine Direct-to-Inject Initiation Attempts Among Patients With Opioid Use Disorder (n = 22).
Defined as having received <4 mg SL in the previous 24 hours and/or positive buprenorphine on available baseline urine drug screen; bStatistical comparisons using Wilcoxon rank-sum testing for continuous variables and Fischer’s exact test for categorical variables with cell values less than 5; cDefined by examining free-text clinician notes describing patient-reported experiences in the first 24 hours after injection and extracting descriptions of withdrawal severity, which we then analyzed and categorized into thematic groups; dDefined as attending a post-direct-to-inject follow-up visit; eDefined as retention on buprenorphine at 7 ± 2 days; fDefined as retention in buprenorphine at 30 ± 7 days.
Of note, 5 attempts (23%) had a COWS score of 0 to 3 prior to injection; 8 (36%) had a score of 4 to 7, 6 (27%) had a score of 8 or greater, and 3 (14%) were unknown. When comparing outcomes across various COWS categories, there was no statistically significant association with post-injection withdrawal experience or retention on buprenorphine at 7 or 30 days (data not shown). Injection doses varied based on provider discretion, including 8 mg (n = 2, 9%), 16 mg (n = 6, 27%), and 24 mg (n = 14, 64%) doses.
Three categories emerged from qualitative categorizations of patient experience after injection: “It felt fine” (n = 6, 27%; eg, “I was surprised, I didn’t get withdrawals”), “I felt unwell but okay” (n = 13, 59%; eg, “24 hours of feeling hot and a little under the weather, but overall tolerable”), and “It felt very rough” (n = 3, 14%; eg, “last night was rough, I vomited once or twice and thought about going out to use”). Among attempts with no buprenorphine prior to injection, experiences most commonly (13/17, 76%) were “unwell but okay,” while those with recent buprenorphine exposure most commonly “felt fine” (3/5, 60%) or “very rough” (2/5, 40%). People who had no buprenorphine prior to injection were more likely to report feeling “unwell but okay,” while those with recent buprenorphine exposure were more likely to report “feeling fine” (P = .005).
Out of 22 direct-to-inject buprenorphine initiation attempts, 100% returned to care, 17 (77%) were retained on buprenorphine at 7 days, and 16 (73%) were retained on buprenorphine at 30 days. Of the 6 attempts with the least significant withdrawal experiences (characterized as “felt fine”), 5 were maintained on buprenorphine at 7 days post-injection and 4 were maintained at 30 days post-injection. Of the 13 attempts with mild-moderate withdrawal experiences (“felt unwell but okay”), 10 were maintained on buprenorphine at 7 days and 30 days post-injection. Of the 3 attempts with the most significant withdrawal (characterized as “very rough”), 100% were retained on buprenorphine at 7 and 30 days. When comparing retention outcomes between patients in the 3 withdrawal groups (“it felt fine,” “I felt unwell but okay,” or “It felt very rough”), there were no statistically significant differences in retention at 7 days (P = 1.00) or retention at 30 days (P = .85), though cell sizes were very small (data not shown).
Discussion
In this case series of 21 patients across 22 initiation attempts, direct-to-inject buprenorphine was generally well tolerated, with most patients reporting mild-to-moderate symptoms in the first 24 hours. Some (3 of 22 attempts, 14%) experienced significant withdrawal, similar to studies of direct-to-inject in ED settings and low-dose buprenorphine initiation protocols in outpatient settings.6,14 This data describes the real-world practice of our clinic sites; there was no uniform protocol regarding injection dose, waiting times between last use and injection, or recommended management for withdrawal symptoms after injection.
We distinguished the 17 attempts of patients with no recent buprenorphine from the 5 attempts of patients who had received some but minimal buprenorphine exposure in the prior 24 hours. This work builds upon a recent study of 7-day extended-release buprenorphine initiations for patients in mild-to-moderate opioid withdrawal in ED settings, where almost half of patients had recent buprenorphine exposure. 6 We found in our case series that patients with recent buprenorphine exposure were more likely to report “feeling fine” in the 24 hours post-injection, while those with no recent buprenorphine were more likely to report feeling “unwell but okay.” While this finding is unadjusted for confounders and is limited by small sample sizes, it may suggest that even minimal recent exposure to buprenorphine may ease the direct-to-inject experience. However, the clinical significance is uncertain as 2 of the 5 patients who had received small amounts of buprenorphine prior to direct-to-inject did have significant withdrawal experiences.
The 3 of 22 attempts that resulted in more significant withdrawal symptoms (categorized as “very rough”) occurred in patients with COWS scores of 0 to 4; in 2 attempts, the patient had a preinjection COWS score of 0 to 3, and in the third attempt, the patient had a COWS score of 4. Ultimately, there were no statistically significant differences between preinjection COWS and subjective withdrawal experiences, though future studies with larger sample sizes should further explore this relationship.
We experienced high percentages of retention at 7- and 30-days. Of note, there was no clear correlation between withdrawal experience and retention. All 3 patients with the most significant withdrawal experiences were maintained on buprenorphine at 7 and 30 days.
The small sample size limited our ability to draw causal inferences between pre-treatment characteristics and outcomes, and our statistical comparisons were not adjusted for potential confounders. In addition, we do not have objective data on withdrawal severity post-injection and were thus unable to assess for precipitated withdrawal. We do not have urine drug screen data for all patients, so rates of recent buprenorphine exposure may have been higher than what was reported, though chart documentation aligned with our categorization of no recent buprenorphine exposure. Finally, there was no standardized direct-to-inject protocol across sites, with heterogeneity in the amount of time since last use and counseling on the management of post-injection withdrawal symptoms. Future studies and clinical practice would benefit from standardized protocols for direct-to-inject and data collection.
In this outpatient sample, direct-to-inject buprenorphine was feasible and generally well tolerated, leading to high rates of retention in buprenorphine treatment. Direct-to-inject buprenorphine may be an option for patients who have previously struggled to initiate buprenorphine. Further research is needed to evaluate the correlation between time since last opioid use and COWS score prior to injection with patient withdrawal experience, as well as on whether the receipt of small doses of buprenorphine prior to injection decreases the risk of significant withdrawal.
Footnotes
Acknowledgements
The authors would like to acknowledge the staff at the San Francisco General Hospital Bridge Clinic, San Francisco Outpatient Buprenorphine Initiation Clinic, Community Behavioral Health Services Pharmacy, San Francisco General Hospital Health Access Point, and Maria X Martinez Health Resource Center for their contributions to this work.
Data Availability Statement
The data supporting the findings of this study are not publicly available due to the small sample size and the potential risk of breaching participant confidentiality. Sharing the dataset could compromise the anonymity of the participants. Therefore, access to the data will not be provided.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Compliance,Ethical Standards,and Ethical Approval
This study was conducted in accordance with the Declaration of Helsinki. The Institutional Review Board (IRB) at the University of California San Francisco determined that this research involved no greater than minimal risk and approved a waiver for informed consent.
